apelin

Gene, mRNA, and precursor

The human APLN gene, location Xq25–26.1, consists of three exons. Human APLN mRNA has 3238 bp nucleotides that encode a preproprotein of 77 aa. Cleavage of the proprotein by subtilisin/kexin 3 (PCSK3 or furin) probably produces APLN-13 (aa 65–77), the mature APLN peptide exerting biological activities. In mammals, the expression of APLN mRNA is seen in the heart, lung, kidney, liver, adipose tissue, intestine, vasdeferens, mammary gland, pituitary, adrenal gland, endothelium, and brain.

Synthesis and release

Hypoxia, diabetic retinopathy, angiopoetin, and FGF2 induce APLN expression. In human adipocytes, APLN expression and secretion are strongly induced under hypoxic conditions, whereas those are decreased by aldosterone.

Receptors

The APLN receptor, APJ, is the seven-transmembrane GPCR. The human APJ consists of 380 aa residues. Although human APJ shows high homology with the human angiotensin receptor 1 (AT-1; 30% in total aa and 54% in transmembrane regions), angiotensin II does not bind APJ. The binding activity of mammalian APLN to AJP: Kd=4.45 nM. The Gi/Go protein is coupled and APLN inhibits the production of cAMP in target cells. The activation of APJ is also mediated by the Akt/mTOR/p70S6 pathway.

Agonists and Antagonists

APLN proprotein (55 aa residues), APLN-36, and APLN-13 (mature apelin). (Ala13)-APLN-13 (functional antagonist).

Biological functions

APLN binds to APJ, located on the cell membrane of various tissues. APLN induces a wide range of biological effects, such as the hypotensive effect through nitric oxide (NO) release, angiogenesis, the stimulation of cardiac contractility, and water intake and diuretic effect. APLN inhibits HIV infection by blocking the HIV coreceptor APJ. Apln-deficient mice are viable, fertile, and showed normal development,whereasApj-deficientmice are not born in the expected Mendelian ratio, and many show cardiovascular developmental defects. Apln-knockout mice show impaired retinal vascularization and ocular development. The APLN-induced hypotensive effect is abolished in Apjdeficient mice. Apj-deficient mice also show increased vasopressor response to the vasoconstrictor angiotensin II. The baseline blood pressure of double mutant mice homozygous for the deletion of both Apj and At1 is significantly higher than that in mice deficient of At1 alone.

Description

Apelin (APLN) is secreted from various tissues in the cardiovascular, digestive, urinary, and CNS, and regulates a wide range of physiological/pathophysiological functions, including cardiovascular function, blood pressure, angiogenesis, and drinking behavior. In 1998, APLN was isolated and characterized from bovine stomach extracts as an endogenous ligand for an orphan GPCR, APJ (putative receptor protein related to the angiotensin receptor, AT1). The peptide sequences of bovine APLN and bovine cDNA encoding preproAPLN were used to identify human APLN.

Clinical Use

The down regulation of APJ is suggested to be a possible cause for the development of heart failure. APLN is indicated to present a future drug target for the treatment of hypertension and heart failure. APJ agonists are expected to be blockers of HIV infection.

Structure and conformation

The human APLN gene encodes a preproprotein of 77 aa residues, containing a signal peptide of 22 aa residues. After cleavage of the signal peptide, the proprotein of 55 aa residues generates several active fragments, including APLN-36 (aa 42–77), APLN-17 (aa 61–77), and APLN-13 (aa 65–77). The APLN-13 is highly active and responsible for the APJ binding and biological activities of mature APLN. So far, 46 different APLN peptides ranging from APLN-55 to APLN-12 have been identified in the bovine colostrum, including C-terminal truncated isoforms. APLN has been identified in mammals, birds, reptiles, amphibians, and teleosts. Mr 8569 (Human preproAPLN), 4195.87 (Human APLN-36), 1550.84 (Human APLN-13). The mature APLN, APLN-13, contains no cysteine or N-glycosylation site. It is soluble in water and physiological saline solution. APLN is a specific substrate of angiotensinconverting enzyme 2 (ACE2).